Process for preparing bicyclo alkyl derivatives

ABSTRACT

A PROCESS FOR THE SYNTHESIS OF BICYCLO ALKYL DERIVATIVES OF THE STRUCTUAL FORMULA:   2,6-(-CH2-X-CH2-),2-R4,3-R1,4-R2,5-R5-CYCLOHEXANONE   IN WICH R1 IS H OR PHENYL, R2 IS H OR ALKYL, R4 IS H PHENYL OR SUBSTITUTED PHENYL IN WHICH THE SUBSTITUENTS ARE HALOGEN, ALKOXY, OR ALKYL, R5 IS   4-(R3-PHENYL)PIPERAZINO OR 4-(R3-PHENYL)PIPERIDINO,   R3 IS H, HALOGEN, ALKOXY OR CF3, AND X IS A POLYCARBON LOWER ALKYLENE RADICAL OF BETWEEN 0 AND 2 CARBON ATOMS INCLUSIVE, COMPRISING THE FOLLOWING REACTION SEQUENCE:   O=CH-CH(-R2)-CH(-R1)-C(-R4)&lt;(-CO-CH2-CH2-X-CH2-) + H-R5   --&gt; (- H2O) R5-CH=C(-R2)-CH(-R1)-C(-R4)&lt;(-CO-CH2-CH2-X-   CH2-) --&gt; (DELTA, DMF OR (I-PR-)OH, (ET-)3-N) 2,6-(-CH2-X-   CH2-),2-R4,3-R1,4-R2,5-R5-CYCLOHEXANONE   THE COMPOUNDS PREPARED ACCORDING TO THE PROCESS OF THIS INVENTION HAVE BENEFICIAL PHARMACOLOGICAL PROPERTIES.

United States Patent Ofice 3,814,767 Patented June 4, 1974 3,814,767PROCESS FOR PREPARING BICYCLO ALKYL DERIVATIVES Frederick Edmund Ward,Elkhart, Ind., assignor to Miles Laboratories, Inc., Elkhart, Ind. NoDrawing. Filed Apr. 7, 1972, Ser. No. 242,227 Int. Cl. C07d 51/70 US.Cl. 260-268 BC 1 Claim ABSTRACT OF THE DISCLOSURE A process for thesynthesis of bicyclo alkyl derivatives of the structural formula:

R R O A in which R is H or phenyl, R is H or alkyl, R is H, phenyl orsubstituted phenyl in which the substituents are halogen, alkoxy, oralkyl, R is R is H, halogen, alkoxy or CF and X is a polycarbon loweralkylene radical of between 0 and 2 carbon atoms inclusive, comprisingthe following reaction sequence:

The compounds prepared according to the process of this invention havebeneficial pharmacological properties.

BACKGROUND OF THE INVENTION This invention relates to the synthesis ofbicyclo alkyl derivatives having beneficial pharmacological properties.

In US. Pat. No. 3,309,370, issued Mar. 14, 1967 to Robert Norman Schutand assigned to the instant assignee, a process is described forsynthesizing certain bicyclo alkyl piperazine derivatives correspondingto some of the compounds prepared by the novel process of thisinvention. Although the process described in US. Pat. No. 3,309,370 wassuitable for preparing a number of bicyclo alkyl products, such processdid not permit the preparation of a compound substituted at the bridgeposition.

SUMMARY OF THE INVENTION Accordingly, it is an object of this inventionto provide a novel process for synthesizing bicyclo alkyl derivativessubstituted at the bridge position.

Another object of this invention is to provide novel bi cyclo alkylderivatives substituted at the bridge position.

A further object of this invention is to provide a novel process forsynthesizing desirable bicyclo alkyl derivatives with readily availablereactants such that there is a satisfactory overall yield.

Other objects and advantages of this invention will become apparent fromthe following description.

This invention is embodied in a process for preparing bicyclo alkylderivatives according to the following process:

in which R is H or phenyl, R is H or alkyl, R is H, phenyl orsubstituted phenyl in which the substituents are halogen, alkoxy, oralkyl, R is 'FJQ or R is H, halogen, alkoxy or CF and X is a polycarbonlower alkylene radical of between 0 and 2 carbon atoms inclusive.

This invention is also embodied in a novel group of bicyclo alkylderivatives that are substituted at the bridge position and moreparticularly at the 5 position of the compound. In the novel compoundsof this invention the radical R, as previously defined, is other than H.

The starting compound used in the novel reaction of this invention maybe prepared by reacting a suitable cycloalkanone with acrolein underbasic conditions to yield a 2-propanal cycloalkanone. The 2-propanalcycloalkanone is reacted with a desirable amine to form an enamine whichis subsequently reacted in a cyclization step in the presence of DMF(dimethylformamide) or i-PrOI-I and triethylamine to form the desiredcompounds.

The propanal is preferably formed by combining the reactants under aninert atmosphere, such as nitrogen, and maintaining the temperaturesubstantially below the reflux temperature. The combined reactants arepreferably stirred for a period of time adequate to permit substantialcompletion of the reaction.

The propanal is then combined with the preselected amine in a suitablesolvent, such as toluene or benzene and heated under reflux for a periodof time sufiicient to permit the removal of the theoretical amount of H0. This H O may be readily collected and measured in a Dean-Starke trap.

The desired product is then formed by heating the enamine prepared inthe previous step in the presence of the DMF or i-PrOH andtriethylamine. This reaction is advantageously carried out attemperature between about 60 C. and C. with stirring for period of about6 to 24 hours or longer.

tion, refer generally to lower alkyl and lower alkoxy each havingbetween about 1 and 5 carbon atoms inelusive. The halogen isbeneficially selected from chlorine or bromine and may be chosen fromother common halogens.

It will be recognized that suitable pharmacologically acceptable saltsmay be readily formed from these compounds according to well knownprocedures. The preparation of a hydrochloride salt is set forth inExample 1. The preparation of other acceptable salts, such as thoseformed from other mineral acids, and organic acids, such as citric acid,maleic acid, oxalic acid and the like, may be'accomplished in a similarmanner.

It has been determined that compounds prepared according to the novelprocess of this invention have beneficial pharmacological activity. InUS. Pat. No. 3,309,370 it was established that these compounds possessactivity as anti-inflammatory and analgetic agents. Further, it has beenobserved that the compounds substituted at the bridge position haveactivity as tranquilizing agents.

The invention will be further described in the following examples whichillustrate the preparation of specific compounds. This invention is notto be construed as limited in scope by these examples, as it will beapparent that numerous other compounds, such as those disclosed in US.Pat. 3,309,370, may be similarly prepared with this novel processwithout departing from the invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS EXAMPLE 12-(4-phenyl-1-piperazyl -5-phenylbicyclo [3.3. 1 nonane-9-one-HC1 A.3-(1 phenyl 2 oxocyclohex l yl)propionaldehyde: To a solution of 38.0 g.(0.21 mole) of 2-phenylcyclohexanone in 200 ml. of Et O at 10 C. underan N atmosphere 3 drops of benzyltrimethylammonium hydroxide (40% inMeOH) was added, followed by dropwise addition of 16.8 g. (0.30 mole) ofacrolein in 50 ml. of Et O. The reaction temperature was not allowed torise above 35 C. during the addition. After 2 hours of stirring, thesolvent was removed in vacuo and the residue distilled. A fraction (9.4g.) with a boiling point of 135- 140 C. (0.1 mm.) was a mixture of thedesired aldehyde and the isomeric 2 hydroxy 5 phenylbicyclo[3.3.1]nonan-9-one; I.R.. (CHCl 3400 (OH), 2720 (CHO), 1725 (C=O, aldehyde) and1710 (C=O, ketone) cm. NMR (CHCI 8.75 (t, 0.5, CHO); the benzylic protonsignal at 3.5 for 2-phenylcyclohexanone was absent.

B. 3(1-phenyl 2 oxocyclohex 1 yl)-1-(4-phenyl-1- piperazyl)propene: Asolution of 8.0 g. (0.034 mole) of compound A and 6.5 g. (0.040 mole) ofl-phenylpiperazine in 100 ml. of toluene was heated under reflux for 3hours during which time the theoretical amount of H was collected in aDean-Starke trap. Removal of solvent in vacuo gave 12.5 g. of theenamine as a redbrown oil; I.R. (CHCI 1715 (C=O, ketone), 1650 (N-O=C)cm.-

C. 2-(4 phenyl 1 piperazyl)--phenylbicyclo[3.3.l] nonane-9-one-HCl:Compound B in 40 ml. of DMF and 10 ml. of triethylamine was stirred at80 C. for 1 day. After removal of the solvent, the residue was stirredin 150 ml. Et O-5% aqueous HCl (2:1) for 18 hours. The hydrochloride wascollected and recrystallized from MeOH yield 0.6 g.; M.P. 198-200 c.;

.551, 1715 emf Analysis.--Calcd. for C H N O-HCl: C, 73.05; H, 7.60; N,6.82. Found; C, 72.62; H, 7.65; N, 6.56.

4 EXAMPLE 2 2-(4-phenyl-1-piperazyl)bicyclo[3.3.1]nonan-9-one A.3-(2-oxocyclohex 1 y1).- 1 (4-phenyl-1-piperazyl-)propene: A mixture of3-(2-oxocyclohex-l-yl)propio'naldehyde (15.4 g.; 0.1 mole), 1phenylpiperazine (16.2 g.; 0.1 mole) and toluene 100 ml.) was refluxedand the water collected in a Dean-Starke trap. The theoretical amount ofH 0 was collected after 4 hours. The solvent was removed in vaco. Theresidue was characterized by means of its I.R. spectrum.

v55? 1700 cm.'

(C=O ketone); 1655 (C=C-N enamine) and no absorption due to the aldehydeC='O.

B. 2-(4-phenyl 1 piperazyl)bicyclo[3.3.1]nonan-9- one: Compound A wasrearranged by heating at 80 C. in a mixture of DMF (80 ml.) andtriethylamine (20 ml.) for 24 hours. The equatorial amine was isolatedby removing the solvent in vacuo, dissolving the residue in 400 ml. of10% hydrochloric acid, washing the acid solution with CHCl to removeneutral impurities and making basic with NH.,OH. The amine precipitatedand was collected by filtration. The solid was recrystallized frommethanol to give 4 g., M.P. 122124 C. The solid was identified as theexpected product by virtue of its infrared spectrum which wassuperimposable on that of an authentic sample prepared by another route.

EXAMPLE 3 Pharmacology Graduated doses of the compound of Example 1 wereadministered intraperitoneally to mice. Tranquilizing activity wasobserved as evidenced by sedation which resulted at a dose of 30 ml. perkg. as judged by the reduced spontaneous motor activity of the mice.This effect was regarded as specific since at this dose muscular coinwhich R is H or phenyl, R is H or lower alkyl of between 1 and 5 carbonatoms inclusive, R is H, phenyl or substituted phenyl in which thesubstituents are halogen, lower alkoxy of between 1 and 5 carbon atomsinclusive, or lower alkyl of between 1 and 5 carbon atoms inclusive, Ris:

R is H, halogen, lower alkox of between 1 and 5 carbon atoms or- Cl, andX is a polycarbon lower alkylene of between 0 and 2 carbon atomsinclusive, the process consisting essentially of combining as a reactionmixture a compound of the formula:

CHRJCHR CHO with an amine of the formula: HR

while removing water from the reaction mixture to form References Citedan enamlne of the formula: UNITED STATES PATENTS O 4 3,108,998 10/1963Poos 260268 BC 5 3,502,669 3/ 1970 Nakamshi 260268 BC c3310 Rz=cHRs3,716,538 2/ 1973 Schut 260268 BC x DONALD G. DAUS, Primary Examinerheating the enamine in a solution of triethylamine and a compoundselected from the group consisting of DMF 10 US. Cl. X.R.

and i-PrOI-I and separating from the solution the desired 260 240 R 29356 598 compound.

